The electrocardiogram (ECG) is based on the electrical activity of the heart muscle cells. In the resting stage, the inside of the cardiac cells has a negative charge compared to the outside of the cells. The resulting voltage difference between the internal and the external spaces of the cell membrane is called transmembrane potential. The discharging of this voltage is known as depolarization and is associated with the start of the contraction of the heart muscle cell fibers. After contraction of the ventricles, the heart muscle cells redevelop substantially the same voltage over the cell membrane. This recovery phase is called the repolarization process of the heart ventricles. An ECG measured from the skin surface measures a total electrical component created by the depolarization and repolarization of the heart's muscular cells.
The repolarization of the heart is made possible in part by ion channels within the myocardial cells of the heart which allow an ion current to redistribute charge. It is highly important that the regulation of the ion currents during the ventricular repolarization process occurs without interference, since a delay in this process or any other abnormalities can lead to a substantially increased risk for sudden cardiac death.
Recently, several important drugs have been removed from the market after it was revealed that these drugs were causing repolarization abnormalities in certain patients. It was determined that these repolarization abnormalities were induced by pharmacological compounds reducing the rapidly activating delayed rectifier potassium current (IKr) of the myocardial cells. The undesirable effect of these repolarization abnormalities was not fully identified in the existing safety assessment studies, which were mainly interested on a time interval which was not necessarily indicative of a change in repolarization morphology. The U.S. Food and Drug Agency (FDA) currently recommends that all pharmaceutical companies test the safety of all new compounds for their potential QT prolonging effect. The QT interval of an ECG encompasses a portion of the repolarization interval. Unfortunately, there is no standard for the measurement of a QT interval, and various techniques used to measure QT interval are not sensitive enough to properly identify a drug associated with a very small yet potentially deadly prolongation of the QT interval. Furthermore, as previously mentioned, QT interval does not quantify changes in the morphology (which includes both amplitude and duration) of the repolarization interval. Consequently, there is a need for other electrocardiographic markers besides QT prolongation for the identification of repolarization abnormalities.